(1) The essential circuit for both item and associative stimulus recognition in any given sensory modality (or across modalities) consists of the relevant cortical sensory processing stream(s), the medial temporal periallocortex (i.e. parahippocampal, perirhinal, and entorhinal cortices), the ventromedial prefrontal cortex, and the magnocellular division of the medial dorsal nucleus of the thalamus. Associative recall, on the other hand, appears now to be organized hierarchically; thus, whereas context-free recall, or fact memory, also seems to depend primarily on the above basic memory circuit, context-rich recall, or event memory, seems to depend in addition on a higher-order circuit superimposed on the basic one and consisting of the hippocampus, mamillary body, anterior thalamic nuclei, and, possibly, cingulate cortex. That item recognition at least does not depend on the higher-order memory circuit is supported by evidence obtained in previous studies of children conducted at the Developmental Cognitive Neuroscience Unit (DCNU) in the Institute of Child Health/University College London. In these experiments we discovered that hypoxic?ischemic events sustained within the first year of life can result in a form of amnesia that appears to differ from the global anterograde amnesia commonly reported in adult-onset cases. The early-onset form, which we labeled 'developmental amnesia' (DA), is characterized by markedly impaired episodic (or event) memory combined with relative preservation of both semantic (or fact) memory and familiarity-based recognition memory, and is associated with medial temporal pathology that seems to be restricted to the hippocampus. In a follow-up study, we found the same selective disorder in children who had sustained hypoxia-induced pathology between the ages of 6 and 14, indicating that the effective age-at-injury for DA to result from hypoxic-ischemic episodes extends from birth to puberty. (2) In a second follow-up study we found that early hippocampal pathology leads to DA only when the volume of this structure is reduced below normal by 20?30% on each side. (3) To measure incidental nonverbal recall in DA, we also studied deferred imitation of action sequences with objects. Like cases of adult-onset amnesia, DA patients performed normally in the spontaneous production of such sequences prior to watching them being modeled but, after seeing them modeled, recalled fewer target actions and action pairs than their matched controls after a 24-hour delay. However, the degree of impairment was less than that reported for the adult-onset cases. (4) That associative recognition in monkeys also does not depend on the higher-order memory circuit (but does require the basic circuit) is supported by new evidence on spatial memory. The new results indicate that the ability to form object-place associations is unaffected by selective, excitotoxic damage to the hippocampus, and yet is severely impaired by ablation of the underlying parahippocampal tissue, revealing the first known mnemonic role for this area. (5) In a follow-up experiment, parahippocampal lesions made with ibotenic acid, which spared the underlying fibers of passage, still yielded a significant impairment in postoperative performance (71% correct compared with 82% correct preoperatively), but this impairment was significantly less than that following the original parahippocampal ablations (60% correct), despite the comparable extent of damage to the parahippocampal cortex in both studies. (6) This result suggests that although the parahippocampal cortex contributes significantly to object-place associations, other areas of the medial temporal lobe, such as the perirhinal and entorhinal cortex, possibly deafferented by undercutting the white matter in parahippocampal-ablation group, might also contribute to that group?s more severe impairment. Preliminary results indicate that ibotenic acid lesions to either perirhinal or entorhinal cortices, both of which receive projections from the parahippocampal cortex, result in an impairment of equal magnitude as that following ibotenic lesions of parahippocampal cortex alone. Thus, multiple cortical areas of the parahippocampal gyrus appear to contribute to the object-place associations, presumably each of them to a different component of this complex task. (7) In an earlier study we examined the extent to which the visual recognition impairment produced by perirhinal cortical ablations might be due to subcortical damage. In that study perirhinal lesions made with ibotenic acid resulted in memory deficits of the same magnitude as that observed after aspiration lesions, even though the amount of damage to the perirhinal cortex was substantially less than that after aspiration lesions (about 50 and 90 percent, respectively); thus it can be concluded that the perirhinal cortex itself is the critical substrate for visual recognition and that there is very little safety factor within this area. (8) More recently we found that monkeys with bilateral removals of the perirhinal cortex failed to relearn one-trial object-reward associations even after 1500 trials, suggesting that the rhinal cortex may also subserve this type of memory. (9) Studies performed earlier at the DCNU and Oxford University demonstrated that half the 30 members of the 3-generational KE family suffer from a speech and language disorder characterized by misarticulation associated with orofacial dyspraxia, which is due in turn to structural brain abnormalities caused by a mutation in the FOXP2 gene. To locate the functional brain abnormalities associated with this mutation, we used both overt and covert verb generation and word repetition during fMRI. The results indicated that whereas the unaffected family members showed the typical left-dominant pattern of activation involving Broca?s area and the neostriatum, among other brain regions, the affected members showed an abnormal distribution of activation located more posteriorly and bilaterally, suggesting that the FOXP2 gene plays a critical role in the development of the frontostriatal system that normally mediates speech.